The candidate (Travis Dunckley) received his Ph.D. in Molecular and Cellular Biology from the University of Arizona in 2000, and has a history of productive research in genetics, molecular biology, and neurobiology. The candidate has expertise in molecular neurobiology and receptor biology. Recent work at the Translational Genomics Research Institute (TGen) has stimulated an interest in elucidating the etiology of neurodegenerative diseases, in particular, the mechanisms whereby neurofibrillary tangles (NFT) contribute to the neuronal cell death and dementia of Alzheimer's disease (AD). AD is a complex genetic disorder that is particularly amenable to genomic analysis via expression profiling. Using microarrays to uncover the molecular bases for NFT formation will require knowledge of: 1) genomics, 2) AD, 3) cell biology, areas in which the candidate has little background. The proposed plan will provide the candidate with a period of mentored research in order to gain expertise in these three areas. The expertise gained in this mentoring period will allow the candidate to attain his long-term goal of developing an independent, multidisciplinary research career in neuroscience, with an emphasis on neurodegenerative mechanisms. In the proposed study it is hypothesized that the CD47 signaling pathway contributes to abnormalities in tau metabolism, NFT formation, and neuronal cell death and dementia in AD. This hypothesis has been generated by stringent expression profiles and will be validated by adding more AD cases to the analysis and by showing that normal, non-demented controls have no involvement of the CD47 signaling cascade (Aim 1). Thereafter, we propose to validate this pathway at the mRNA, protein, and functional levels (Aim 2). Importantly, these experiments will identify numerous new and much needed potential targets for the treatment of AD. Dietrich Stephan, Ph.D. (mentor) will provide training in genomics and functional validation of microarray data. Joseph Rogers, Ph.D. (co-mentor) will provide training in AD and cell biological techniques. Additional resources and techniques in viral siRNA delivery and tau cell lines and phosphorylation assays will be received through continued ongoing collaborations (Dale Schenk and Michael Hutton). The many resources available to the candidate at TGen, in combination with the strong research programs of the mentor, co-mentor, and collaborators, will provide the candidate with the comprehensive training necessary to achieve his career goals and, hopefully, arrive at new therapeutic modalities for the largest cause of age-related dementia - Alzheimer's Disease.